Oxidation, nitrosation, and nitration of serotonin by nitric oxide-derived nitrogen oxides: biological implications in the rat vascular system.
Because NO is not very reactive in an oxygen-free buffer, a significant part of serotonin (5-HT) is transformed by NO in nondeaerated phosphate buffer, at pH 7.4, into (4-serotonyl)-4-serotonin, 4-nitrososerotonin, and 4-nitroserotonin. Dimerization and above all nitrosation occur through the HNO2 reaction in the pH 4-6 range, possibly via radical mechanism involving N2O3. 5-HT is readily a substrate for nitrosation by HNO2 or N2O3, whereas tyrosine was described as not very reactive under the same conditions. Peroxynitrite converts 5-HT to the (4-serotonyl)-4-serotonin and to the 4-nitro derivative. In order to evaluate whether such structural modifications could modulate the biological properties of 5-HT, arterial pressure was measured after i.v. bolus injection of these derivatives to anesthetized rats. Injections of the 4-nitroso- and 4-nitro-5-HT resulted in first a brief hypotensive response and did not give the subsequent hypertensive and hypotensive phases observed with 5-HT. Finally, when tested on some cloned rat 5-HT receptors stably transfected into LMTK- cells, both 4-nitroso and 4-nitro derivatives behaved as agonists and antagonists toward 5-HT1B and 5-HT2B receptors, respectively.
Blanchard
B
B
Institut de Chimie des Substances Naturelles, CNRS, Gif sur Yvette, France.
Dendane
M
M
Gallard
J F
JF
Houée-Levin
C
C
Karim
A
A
Payen
D
D
Launay
J M
JM
Ducrocq
C
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D019281:Dimerization; D005609:Free Radicals / Q000378:metabolism; D005720:Gamma Rays; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D009608:Nitrous Acid / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D014162:Transfection / Q000235:genetics
C115055:(4-serotonyl)-4-serotonin; C115053:4-nitro-5-HT; C115054:4-nitroso-5-HT; D005609:Free Radicals; D009566:Nitrates; D009574:Nitro Compounds; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D011985:Receptors, Serotonin; C039642:peroxynitric acid; D009569:Nitric Oxide; D012701:Serotonin; D010100:Oxygen; D009608:Nitrous Acid